Abstract: IgA nephropathy (IgAN) is characterized by mesangial IgA1 immune deposits that originate from circulating immune complexes containing aberrantly-glycosylated IgA1, i.e., IgA1 with galactose-deficient O-glycans (Gd- IgA1). Several lines of evidence suggest a direct causal relationship between aberrant glycosylation, the formation of immune complexes containing aberrantly glycosylated IgA1, their deposition in the mesangium, and renal injury in IgAN. We have now localized the primary defect to IgA1-secreting cells from IgAN patients and our preliminary data indicate that serum Gd-IgA1 levels are a highly heritable biomarker of IgAN. Our initial genetic studies have identified two genomic regions that influence this trait in IgAN. Preliminary genome-wide expression profiling has demonstrated that 65% of the genes from these two chromosomal intervals are expressed in IgA1-producing cell lines with 19 of them being differentially expressed in cells that produce Gd- IgA1. We hypothesize that a high level of serum Gd-IgA1 defines an endophenotype that can be used to identify the genetic basis for this disease. We have established a standardized sensitive technique for high through-put analysis of Gd-IgA1 in the serum; IgA1-secreting cell lines from patients with IgAN and healthy controls that permit confirmation of genetic defects with molecular effects in vitro; and extensive collaborations that provide access to well-characterized IgAN patients and disease controls. We therefore propose to further establish the sensitivity and specificity of the serum Gd-IgA1 test in multiple existing independent cohorts, and, using genetic and biochemical studies, determine the contribution of the identified loci to the sporadic and familial forms of IgAN. We will then prioritize genes within these two linkage intervals by gene expression analysis and functional studies in our IgA1-producing cell lines. Finally, we will stratify cases and controls by Gd-IgA1 levels and perform genetic association studies to identify IgAN susceptibility alleles. Relevance: IgAN is the most common primary glomerulonephritis and leads to loss of renal function in 20% to 40% of patients. Our current inability to describe the pathogenesis of IgAN at the molecular level is a major barrier to the development of IgAN-specific treatments. The proposed studies will provide the foundation for the future development and testing of disease-specific interventions and advance the quality of care for IgAN patients.